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Endocannabinoid-Mediated Neuromodulation in the Olfactory Bulb: Functional and Therapeutic Significance

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Endocannabinoid-Mediated Neuromodulation in the Olfactory Bulb: Functional and Therapeutic Significance International Journal of Molecular Sciences Review Endocannabinoid-Mediated Neuromodulation in the Olfactory Bulb: Functional and Therapeutic Significance Naina Bhatia-Dey and Thomas Heinbockel * Department of Anatomy, Howard University College of Medicine, Washington, DC 20059, USA; [email protected] * Correspondence: [email protected]; Tel.: +1-(202)-806-0058 Received: 11 March 2020; Accepted: 17 April 2020; Published: 19 April 2020 Abstract: Endocannabinoid synthesis in the human body is naturally occurring and on-demand. It occurs in response to physiological and environmental stimuli, such as stress, anxiety, hunger, other factors negatively disrupting homeostasis, as well as the therapeutic use of the phytocannabinoid cannabidiol and recreational use of exogenous cannabis, which can lead to cannabis use disorder. Together with their specific receptors CB1R and CB2R, endocannabinoids are major components of endocannabinoid-mediated neuromodulation in a rapid and sustained manner. Extensive research on endocannabinoid function and expression includes studies in limbic system structures such as the hippocampus and amygdala. The wide distribution of endocannabinoids, their on-demand synthesis at widely different sites, their co-existence in specific regions of the body, their quantitative differences in tissue type, and different pathological conditions indicate their diverse biological functions that utilize specific and overlapping pathways in multiple organ systems. Here, we review emerging evidence of these pathways with a special emphasis on the role of endocannabinoids in decelerating neurodegenerative pathology through neural networks initiated by cells in the main olfactory bulb. Keywords: Alzheimer’s Disease; endocannabinoids; neurodegeneration; neuromodulation; neural dysfunction; odor; olfactory bulb; olfactory system; synaptic plasticity 1. Introduction The endocannabinoid system is a unique system of neuromodulation that has been characterized mainly in the last thirty years starting with the identification of its main and associated receptor components, ligands, agonists, antagonists, participating in synthesis and degradation, cofactors, transporter proteins, activating and inhibitory cytoskeletal components, transcription factors and their modifiers [1–3]. Both endogenous and exogenous ligands of the endocannabinoid system affect standard physiological processes such as pain, inflammation, nausea, and feeding behavior together with psychoactive functions such as memory, emotion, cognition, and reward [2,3]. In general, endocannabinoids function as retrograde messengers that mediate short-term synaptic plasticity through two distinct mechanisms: depolarization-induced suppression of inhibition (DSI) and depolarization-induced suppression of excitation (DSE). DSI involves a reduction of gamma-aminobutyric acid (GABA) neurotransmitter release from presynaptic neurons resulting in the suppression of inhibition in postsynaptic neurons [4]. DSI has been demonstrated in several brain regions such as the hippocampus, amygdala, and the main olfactory bulb. In the main olfactory bulb, DSI allows olfactory bulb output neurons to be transiently relieved from inhibition, potentially to facilitate the detection of weak odor signals [5,6]. In contrast, DSE leads to reduction of glutamate release, thereby suppressing glutamate-mediated excitation at neural synapses [7]. Both signaling pathways Int. J. Mol. Sci. 2020, 21, 2850; doi:10.3390/ijms21082850 www.mdpi.com/journal/ijms Int. J. Mol. Sci. 2020, 21, 2850 2 of 13 indicate the participation of the endocannabinoid system in a site-specific manner affecting specific neurotransmitter release in each case. Based on site-specific on-demand synthesis in many tissues and the involvement of multiple cell types where retrograde messenger activity affects synaptic plasticity, there is a surge of research activity to identify endocannabinoid functions in neurodegenerative diseases in a bidirectional approach: first, in disrupting the progression of symptoms of neurodegenerative pathology and second, in applying therapeutic intervention/s to modify erratic behavioral patterns that may emerge as consequence of progressing neurodegenerative pathology. There is extensive experimental evidence regarding quantitative and qualitative differences in levels of endocannabinoids, their receptors concentrations, and metabolizing enzymes in diverse tissue types for human patients of [8,9] as well as in mammalian models of neurodegenerative and related conditions [2,10–12]. Based on these spatial and temporal patterns of expression, endocannabinoids are thought to participate in diverse biological functions in specific cells layers of many tissues. The hypothesis is that the molecular targets of endocannabinoids have diverse locations to modulate physiological processes and behavior patterns in a cell- and tissue-specific manner. Pre-clinical research on depression and neurodegenerative pathology compares the rodent frontal cortex after bulbectomy (removal of olfactory bulb) with pathological features seen in human brains of patients having neurodegenerative and/or neuropsychological disorders with aim of collecting comparable neuroanatomical, electrophysiological and molecular data [13]. For the last two decades, through studies exploring the advantages of various animal models for experimental manipulation, the olfactory system has emerged as a system to precisely analyze cellular, molecular, and neurological alterations correlated with specific patterns of behavior modulation [14–16]. Exposure to food odors by a social partner as a means of social transmission of food preferences evokes plasticity in olfactory bulb networks at the level of dendrodendritic synapse [17]. Specifically, such an experimental approach induces a glomerulus-specific long-term potentiation (LTP) at dendrodendritic synapses between GABAergic granule cells and mitral cells, the key output neurons in the olfactory bulb. The results indicate the existence of a synaptic substrate for a socially conditioned long-term memory at the first central relay for olfactory processing. Here, sensory cues are associated with social context through a socially relevant synaptic modification in the olfactory bulb. The LTP was blocked by deleting synaptotagmin, a calcium sensor or by deleting insulin-like growth factor 1 (IGF1) receptor in the olfactory bulb. In a transgenic mouse model that specifically expresses a calcium sensor in olfactory bulb neurons, odor evoked activity shows a widespread lateral propagation due to blockage of dendrodendritic inhibition [18]. Despite the detection of cannabinoid type 1 receptor (CB1R) and cannabinoid type 2 receptor (CB2R) mRNA and protein in the olfactory epithelium, olfactory-mediated behavior remained normal in knockout mouse models of these receptors [19]. These findings suggest that the olfactory bulb is a site of synaptic plasticity with a functional role of the endocannabinoid system. The authors further show transport of such local effects to the limbic system. Analysis of olfactory dysfunction in neurodegenerative pathology is becoming more important [20–22], especially since many neurodegenerative disorders exhibit olfactory deficits and olfactory dysfunction prior to the onset of neurodegenerative pathology [23]. Progressive tauopathy, i.e., the appearance of specific brain degeneration as a typical feature of Alzheimer’s disease, is detectable following olfactory dysfunction [24]. Olfactory deficits and dysfunction are known as prodromal symptoms of other neurodegenerative disorders including Parkinson’s disease (PD) as well as Alzheimer’s disease (AD) [25,26]. In addition, quantitative proteomic analysis of pathological alterations in the olfactory bulbs of patients suffering with progressive supranuclear palsy (PSP) and frontotemporal lobar degeneration, FTLD-TDP43, revealed an imbalance in survival signaling for both pathologies [27]. As olfactory bulb cell layers participate in initial information processing, they are the first contact point for external stimuli/stressors and serve as gateway for prion-like propagation of odorants, and pathogens as well as misfolded and unfolded proteins. Each of these may lead to neurodegenerative pathology, either individually or as combinatorial trigger [25]. Single Int. J. Mol. Sci. 2020, 21, 2850 3 of 13 cell transcriptome analysis during mouse olfactory neurogenesis in early development reveals that expression of olfactory receptor genes becomes progressively restricted to one gene per neuron in each mature neuron instead of several receptor genes that express in immature neurons [28,29]. Recently, the adult human olfactory bulb has become a popular and active site for the study of functional genomic influences on neurogenesis [30]. This is evident with CB1R and CB2R expression and functional studies using knockout mouse models [19]. In the mouse olfactory epithelium, immunohistochemistry shows diffuse CB1R protein expression, indicating protein localization in both neuronal and non-neuronal cell types. Whereas cell type specific CB2R protein expression remained ambiguous due to non-specific antibodies, it is evident simply by immunoblot, possibly due to CB2R expressing immune cells in the lamina propria [19]. These findings have established olfactory bulb cell layers as a dynamic site for modulation of molecular signaling at the single cell level throughout the lifetime of an organism. While the functional participation of the endocannabinoid system in neuronal
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